DIFFERENTIAL THYMIC SELECTION OUTCOMES STIMULATED BY FOCAL STRUCTURALALTERATION IN PEPTIDE MAJOR HISTOCOMPATIBILITY COMPLEX LIGANDS/

The T lineage repertoire is shaped by T cell receptor (TCR)-dependent positive and negative thymic selection processes. Using TCR-transgenic (N15tg) beta(2)-microglobulin-deficient (beta(2)m(-/-)) RAG-2(-/-) H- 2(b) mice specific for the VSV8 (RGYVYQGL) octapeptide bound to Kb, We identified a single weak agonist peptide variant V4L (L4) inducing ph enotypic and functional T cell maturation. The cognate VSV8 peptide, i n contrast, triggers negative selection. The crystal structure of L4/K -b was determined and refined to 2.1 Angstrom for comparison with the VSV8/K-b structure at similar resolution, Aside from changes on the p4 side chain of L4 and the resulting alteration of the exposed K-b Lys- 66 side chain, these two structures are essentially identical. Hence, a given TCR recognizes subtle distinctions between highly related liga nds, resulting in dramatically different selection outcomes. Based on these finding and the recent structural elucidation of the N15-VSV8/K- b complex, moreover, it appears that the germ-line V alpha repertoire contributes in a significant way to positive selection.